Chromatin Assembly Factor 1b Critically Controls The Early Development But Not Function Acquisition Of Invariant Natural Killer T Cells In Mice

CD4(+)CD8(+) double-positive thymocytes give rise to both conventional TCR alpha beta(+) T cells and invariant natural killer T cells (iNKT cells), but these two kinds of cells display different characteristics. The molecular mechanism underlying iNKT cell lineage development and function acquisition remain to be elucidated. We show that the loss of chromatin assembly factor 1B (CHAF1b) maintains the normal development of conventional TCR alpha beta(+) T cells but severely impairs early development of iNKT cells. This dysregulation is accompanied by the impairment in chromatin activation and gene transcription at V alpha 14-J alpha 18 locus. Notably, ectopic expression of a V alpha 14-J alpha 18 TCR rescues Chaf1b-deficient iNKT cell developmental defects. Moreover, cytokine secretion and antitumor activity are substantially maintained in V alpha 14-J alpha 18 TCR transgene-rescued Chaf1b-deficient iNKT cells. Our study identifies CHAF1b as a critical factor that controls the early development but not function acquisition of iNKT cells via lineage- and stage-specific regulation.